Acyl amidine and acyl, guanidine substituted biphenyl derivatives

Abstract

Novel compounds are disclosed having the formula ##STR1## and wherein R 1 , R 2 and R 3 are as defined herein. These compounds inhibit the action of angiotensin II and are useful, therefore, for example, as antihypertensive agents.

What is claimed is: 
     
       1. A compound of the formula ##STR20## pharmaceutically acceptable salts thereof; where R 1  is hydrogen, --COOH, --NHSO 2  CF 3 , ##STR21## R 2  is H, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F; phenylalkenyl wherein the aliphatic portion is 2 to 6 carbon atoms; --(CH 2 ) m  -imidazol-1-yl; --(CH 2 ) m  -1,2,3-triazolyl optionally substituted with one or two groups selected from CO 2  R 7  or alkyl of 1 to 4 carbon atoms; --(CH 2 ) m  -tetrazolyl; --(CH 2 ) n  OR 6  ; ##STR22## R 3  is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO 2  R 7  ; cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms; cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms; --(CH 2 ) s  Z(CH 2 ) m  R' (wherein R' is H, C 1-6  alkyl, C 3-6  cycloalkyl, C 2-4  alkenyl or C 2-4  alkynyl) optionally substituted with F or CO 2  R 7  ; benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro; R 6  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;   R 7  to H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;   R 8  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;   R 9  is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH 2 ) p  C 6  H 5 , OR 11  or NR 12  R 13  ;   R 10  is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH 2 ) p  C 6  H 5  ;   R 11  is H, alkyl of 1 to 6 carbon atoms, cyclalkyl of 3 to 6 carbon atoms, phenyl or benzyl;   R 12  and R 13  independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, α-methylbenzyl, or taken together form a ring of the formula ##STR23## Q is NR 14 , O or CH 2  ; R 14  and R 15  are independently H, alkyl, aryl, aralkyl or cycloalkyl;   R 16  is C 1-6  alkyl, --NR 17  R 18  or ##STR24## R 17  and R 18  are independently H, C 1-6  alkyl, benzyl or taken together are 3 to 6 carbon atoms forming a 4- to 7-membered ring with the nitrogen atom to which they are attached;   R 19  is H, C 1-5  alkyl, phenyl;   R 20  is --CN, --NO 2  or --CO 2  R 7  ;   Y=O or S;   Z=O, NR 6  or S;   m is 1-5;   n is 1-10;   p is 0-3;   s is 0-5; and   t is 0 or 1.   
     
     
       2. The compound of formula I as recited in claim 1 wherein R 1  is independently COOH or tetrazole;   R 2  is selected from methyl, ethyl, --CH 2  OH; and   R 3  is selected from n-butyl, n-propyl, NH-n-propyl.   
     
     
       3. The compound of formula I as recited in claim 1 wherein A is ##STR25## and R 1  is COOH; R 2  is methyl; and   R 3  is propylamino.   
     
     
       4. The compound of formula I as recited in claim 1 having the name 4'-[[4,5-Dihydro-5-methyl-4-oxo-2-(propylamino)-1H-imidazol-1-yl]methyl]-[1,1'-biphenyl]-2-carboxylic acid, trifluoroacetate (1:1) salt. 
     
     
       5. A pharmaceutical composition comprising a compound of formula I as recited in claim 1 and a pharmaceutically acceptable carrier. 
     
     
       6. A method of treating hypertension comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim 5. 
     
     
       7. A method for treating congestive heart failure comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim 5. 
     
     
       8. A method for preventing cardiac hypertrophy comprising administering to a mammalian specie in need thereof a therapeutically effective amount of a composition of claim 5.